Neuroinflammation and local pro-inflammatory mediators are associated with neurodegenerative diseases as well as traumatic brain injury (1). In both scenarios, treatment with docosahexaenoic acid (DHA) reduces inflammation and local tissue injury. For example, DHA reduces the damage from impact acceleration injury and reduces β-amyloid precursor, a marker of axonal injury in vivo relevant in traumatic brain injury (2). Also, DHA reduces ischemic stroke in rats via production of neuroprotectin D1, which acts on leukocytes and reduces leukocyte infiltration, leukocyte-mediator tissue damage and regulates NF-κB (3). Neuroprotectin D1 stimulates neuronal stem cell differentiation (4) and has potent anti-inflammatory and pro-resolving actions in several in vivo disease models (5-7). D series resolvins are biosynthesized from DHA in brain tissue and resolving inflammatory exudates (7,8). Resolvin D1 and resolvin D2 display potent stereoselective actions that are anti-inflammatory, pro-resolving and reduce pain signaling, and act in the pico- to nanomolar range in vivo, a dose range where DHA itself displays no demonstrable action (9-11). Hence, the metabolome and metabolic fate of DHA is of interest in the resolution of pain, inflammation and tissue injury.
Another metabolic fate of DHA in brain is conversion to docosahexaenoyl ethanolamine (DHEA), which is thought to be produced by the same pathway as N-acyl-arachidonoyl-ethanolamide (AEA, anandamide) (12). DHEA is directly related to dietary intake of DHA and is enriched in brain tissue at comparable levels to AEA (13). AEA is an endocannabinoid that regulates neurofunctions and the immune system via CB1 and CB2 receptors (14-17).
Therefore, a need exists for a further understanding of, an exploration or and identification of new useful materials previously not appreciated as potent biological mediators of interest.